Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, cancer susceptibility and radiation sensitivity (Gatti et al., Medicine 70: 99-117, 1991). The disease has a well-defined phenotype, in most cases easily diagnosed and shows complete penetrance. The disease frequency has been estimated at 1/40,000-1/100,000 live births (Swift et al., N Engl J Med 325: 1831-36, 1991). The gene responsible for AT was localized by linkage analysis to within 300 kb at chromosome 11q23.1, using an international consortium of .about.200 families (Gatti et al., Nature 336: 577-580, 1988; Gatti et al., Intl J Radiat Biol 66: S57-S62, 1994; Lange et al., Am J Hum Genet 57,112-119, 1995; Uhrhammer et al., Am J Hum Genet 58: 103-111, 1995). Savitsky and workers identified a gene in this region, ATM, encoding a very large protein (.about.350 kDa), with a transcript of 12 kb and alternative splicing (Savitsky et al., Science 268: 1749-1753, 1995; Savitsky et al., Hum Mol Genet 4: 2025-2032, 1995). ATM stands for ataxia-telangiectasia mutated. The gene shows homology with protein kinases in yeast (TEL-1), Drosophila, and human (DNA-PK) and is most closely related to DNA-PK and TEL-1 (Savitsky et al., Science 268: 1749-1753, 1995; Savitsky et al., Hum Mol Genet 4: 2025-2032, 1995; Lehmann et al., Trends Genet 11: 375-377, 1995; Zakian, Cell 82: 685-687, 1995; Lavin et al., Trends Biol Sci 20: 382-383, 1995; Keith et al., Science 270: 50-51, 1995). SEQ ID NO:1 is the nucleotide sequence encoding the ATM protein, corresponding to GenBank Accession No. U33841. The open reading frame is 9168 nucleotides. There is a 3' untranslated region (UTR), and a 5' UTR. SEQ ID NO:2 is the amino acid sequence of the deduced ATM protein. It has 3056 amino acids. The ATM gene product contains a phosphatidylinositol-3 kinase (PI-3) signature sequence at codons 2855-2875. Mutation analyses in the initial report by Savitsky et al., Science 268: 1749-1753, 1995, used restriction endonuclease fingerprinting (REF) to identify mutations in the reverse-transcribed 5.9 kb carboxy-terminal end, which included the PI-3 signature sequence, of the 10 kb transcript that was available at that time (Savitsky et al., Hum Mol Genet 4: 2025-2032, 1995). Both in-frame and frameshift mutations were found. Because the methodology used for screening for mutations biases the types of mutations found, there is a need to use different screening methods to identify further mutations in the ATM gene.
These and other objects of the invention will be apparent to one of ordinary skill in the art upon consideration of the specification as a whole.